Aromatic mercury cyclic alkaloid compounds and method of making them



Patented June 29, 1937 2.085064 ABOMATIC MERCURY CY CLIC COMPOUNDS THEMCarl N. Andersen,

to Lever Brothers Maine No Drawing.

AND METHOD OF Application January 21, 1935,

Serial No. 2,757

15 Claims. (Cl. 260-13) The present invention relates to the productionof certain new organic mercury compounds, and more particularly toaromatic mercury derivatives of cyclic alkaloids.

It is an object of my invention to produce new organic mercury compoundsuseful as germicides and for other therapeutic purposes.

I have discovered that if the essential radical of an aromatic mercurycompound, consisting of an aromatic nucleus to which mercury is directlyattached, is introduced into certain cyclic alkaloids, compounds areproduced which have I extremely high potency as antiseptics andgermicides, and at the same time are characterized by relatively lowtoxicity and other desirable properties.

The above mentioned aromatic mercury cyclic alkaloids contain theessential radical RHglinked to a cyclic alkaloid.

b R represents an aromatic structure which may be an aromatic nucleuswith or without side chains, and the expression aromatic structure usedherein is intended to be generic and include an aromatic nucleus with orwithout side chains.

The aromatic structure is one of the type in which none of the nuclearor side chain carbon atoms has direct linkage with any element otherthan hydrogen, carbon or mercury. R may stand for the phenyl group,CsHs, or for an aromatic hydrocarbon having a nucleus similar to thephenyl hydrocarbons, as for example, polycyclic hydrocarbons in whichall of the nuclear carbon atoms, other than the one attached to mercury,and any side chain carbon atoms, have their valences satisfied by eithercarbon or hydrogen.

Examples are the diphenyl, tolyl, xylyl and naphthyl groups.

The complex structure of many of the alkaloids renders theirinvestigation a matter of extreme diificulty, and despite a century ofresearch, the constitution of all of these substances is not known.However, enough is known of their structure so that they may be groupedinto two main classes: aliphatic and cyclic. Aliphatic alkaloids includederivatives of purine, such as 45.xanthine, theophylline, andtheobromine. The

structure of alkaloids of this type is better understood, and in generalthey are imides, which are disclosed and claimed in my copendingapplications, Serial Nos. 754,373 and 754,374, both filed November 22,1934.

" My present invention is concerned with the more complex cyclicalkaloids. One authority has classified the compounds which have beenidentified as to structure into four main groups.

1. Derivatives of zwridz'na-Examples are piperine. C1-1HmOaN;

MAKIN ID G Water-town, Masa, assignm- Company, a corporation of conline,CIHlIN; pilocarpine,

C11HisO2N2; and nicotine, CmHuNz.

2. Tropine group or alkaloids with condensed tetrahydropyrrole andpiperidine chains.--Examples are atropine, C1'1H2sOaN;

cocaine,

C11Hz1O4N; ecgonine, CQHlBOSN; and norecgonine.

CaHnOaN.

There are many other cyclic alkaloids whose exact structure is as yetunknown.

Examples are aconitine, cytisine, and colchicine.

I have investigated most of the above named compounds by reacting themwith an aromatic mercury compound of the type described so as to producea. corresponding aromatic mercury alkaloid. I have prepared asufficiently representative number of these compounds to lead me tobelieve that all of the cyclic alkaloids can be employed to produce mynovel aromatic mercury alkaloids. I therefore intend my invention toinclude all cyclic alkaloids whether their exact structure is known ornot.

The compounds so prepared have a greater or lesser, but always arelatively high degree of antiseptic and germicidal properties.

The expression cyclic alkaloids is intended to be generic and includeany of the above named compounds, their homologues and equivalents.

These aromatic mercury alkaloids may be prepared by reacting a solublemercury compound containing the aromatic mercury radical with thealkaloid. An aromatic mercury hydroxide or any soluble salt such as theacetate or lactate is preferably employed. The cyclic alkaloid and thearomatic mercury compound are brought together in a common solvent whichwill not enter into the reaction.

loids so produced, being The aromatic mercury alkarelatively insoluble,will precipitate or can be precipitated by concentrating the solution.The precipitate can be filtered,

washed and dried.

More detailed instructions relating to the process will be given laterin connection with several specific examples.

I have mentioned before that the alkaloids are very complex instructure, and their chemical properties, structure, and the reactionsin which they enter are determined only with extreme difficulty. Even inthe case of alkaloids whose structure is known, I have not so far beenable to determine the exact position in the alkaloid molecule in whichthe aromatic mercury radical enters or the particular chemical mechanismof Ezcample 1 15.65 grams of piperine is dissolved in alcohol. To thisis added 16.08 grams of phenylmercury acetate and a white crystallineprecipitate results upon the reaction of the two compounds. Theprecipitate is separated by filtration and washed well with warm waterand dried. Upon recrystallization from alcohol it melts at 108- 110 C.The compound is the phenylmercury derivative of piperine.

Example 2 4.55 grams of hydrastinine is dissolved in 50 cc. of alcohol.If hydrastinine hydrochloride is used, 5.31 grams should be treated withthe theoretical amount of sodium hydroxide to liberate the free base. Tothis solution is added 5.88 grams of phenylmercury hydroxide dissolvedin one liter of water. Heat may be employed to dissolve thephenylmercury hydroxide and the solution may be filtered before mixingwith the hydrastinine. No precipitate results upon the mixture of thetwo solutions, but the solution assumes a yellowish tint. The materialis evaporated to A; its volume and allowed to stand, out of which ayellowish solid separates. The precipitate is separated by filtration,after which it is washed well with warm water and a few cc. of alcohol,and dried. Upon recrystallization from alcohol it softens at 232 C. andmelts at 238 C. The compound is the phenylmercury derivative ofhydrastinine.

Example 3 3.36 grams of phenylmercury acetate is dissolved in 200 cc. ofwater and heated until solution is complete. The solution is filtered tore-' move any insoluble material. To the filtrate is added an alcoholicsolution containing 2.89 grams of atropine. A beautiful whitecrystalline precipitate results. The mixture is allowed to stand, afterwhich it is filtered and the precipitate washed well with warm water anddried. It has a melting point of -155 C. The compound is thephenylmercury derivative of atropine.

Example 4 3.36 grams of phenylmercury acetate is dissolved in 200 cc. ofwater and heated until solution is complete. The solution is filtered toremove any insoluble material. To this solution is added 3.56 grams ofquinine dissolved in alcohol.

The solution is boiled to remove the alcohol and upon standingbeautiful, shiny, scaly crystals separate. These are removed byfiltration, washed well with warm water and dried. The

compound has a melting point of l28-132 C. and

is the phenylmercury derivative of quinine.

Example 5 hydroxide solution and a voluminous white precipitate resultswhich is separated by filtration, washed well with warm water and dried.It melts at 238-241 C. and upon recrystallization from alcohol has amelting point of 249 C. The compound is the phenylmercury derivative ofecgonine.

Emmple 6 4.13 grams of narcotine is dissolved in 20 cc.

of chloroform. To this solution is added 3.36 grams of phenylmercuryacetate dissolved in 200 cc. of water. The mixture is heated to expelthe chloroform and then allowed to cool. Well defined crystals separatewhich are removed by filtration, washed well with warm water and dried.The material melts at 138-150 C. and upon recrystallization from alcoholmelts at 171.5 C. The compound is the phenylmercury deriva tive ofnarcotine.

The reacting materials are employed in substantially theoreticalquantities. If desired, in some instances, 10% excess of the alkaloidmay be employed in order to insure the complete conversion of thephenylmercury compound.

Any suitable solvent in which the reacting componets are soluble may beused as the medium for carrying out the reaction. As most alkaloids aresoluble in one of the alcohols, or mixtures of an alcohol and water,this medium is convenient.

However, water or other solvents, such as acetone, chloroform, ormixtures of these with each other or with water, may be employed if thealkaloid and the phenylmercury compound are soluble therein. The processmay be carried out at any temperature, for example, room temperature. Inmost cases I find, however, that the use of heat facilitates thesolution of the reacting components and speeds the reaction.

From the description of the specific examples it will be readilyapparent to one skilled in the art how the other members of the cyclicalkaloid group may be reacted with an aromatic mercury compound toproduce mercury alkaloids of analogous structure. All of the compoundsproduced as above described are characterized by highly satisfactoryantiseptic and germicidal properties. Because of their high germicidalvalue they may be used in extreme dilutions.

In addition to their germicidal value they may have other uses inmedicine, for example the cocaine derivative also functions as a localanesthetic.

All of the compounds produced as above described are characterized byextraordinarily high iii) potency as germicides. Tests to determine theefficacy of certain of them in killing B. typhosus and Staph. aureuswere carried on under the following conditions:

Aqueous solutions of varying dilutions from 1:10.000 upward untilkilling ceased, were made up.

These dilutions were employed in the conduct of the tests by thefollowing methods:

Circular 198, U.'S. Dept. of Agriculture, Dec. 1931, described as F. D.A. method against Eberthella typhi (typhoid bacillus) at 37 C. and F. D.A. Special method against Staph. aureus at 37 C.

As illustrative of the potency of the compounds, the killing power ofthe following compounds is given merely as illustrative:

The figures represent the maximum dilutions at which killing in 15minutes resulted:

B. ty- Staph. phosus aureus Phenylmercury ecgonine 1:60,000 1:20,000Phenylmercury coniine 1:80,000 1:30,000

All of these compounds retain a high degree of germicidal activity whenincorporated in soap and various other menstrums employed in makinggermicidal compositions.

When these new compounds are to be used directly as germicides they maybe employed in aqueous or other solutions or they may be formed intovarious preparations such as mouth washes, tooth pastes, soaps,ointments, etc.

I claim: 1. A method of making aromatic mercury cyclic alkaloidcompounds which comprises reacting in solution a cyclic alkaloid with acompound selected from the group consisting of the aromatic mercuryhydroxides and aromatic mercury soluble salts of soluble acids in whichthe mercury is directly attached by one of its valences to the negativeradical in the compound and attached by its other valence to a carbonatom of an aromatic structure in which none of the carbon atoms hasdirect linkage with any element other than hydrogen, carbon and mercury.

2. A method of making aromatic mercury cyclic alkaloid compounds whichcomprises reacting in solution a cyclic alkaloid with an arcmaticmercury hydroxide in which the mercury is directly attached to a carbonatom of an arcmatic structure in which none of the carbon atoms hasdirect linkage with any element other than hydrogen, carbon and mercury.

3. A method of making aromatic mercury cyclic alkaloid compounds whichcomprises reacting in solution a cyclic alkaloid with an arcmaticmercury soluble salt of a soluble acid in which the mercury is directlyattached to a carbon atom of an aromatic structure in which none of thecarbon atoms has direct linkage with any element other than hydrogen,carbon and mercury.

4. A method of making aromatic mercury cyclic alkaloid compounds whichcomprises reacting in solution a cyclic alkaloid with an arcmaticmercury acetate in which the mercury is directly attached to a carbonatom of an arcmatic structure in which none of the carbon atoms hasdirect linkage with any element other than hydrogen, carbon and mercury.

5. A new aromatic mercury compound in which the radical RHg-is attachedto a cyclic alkaloid, where R represents an aromatic structure to acarbon atom of which the mercury is directly attached and in which noneof the carbon atoms has direct linkage with any element other thanhydro-gen, carbon and mercury.

6. A new aromatic mercury compound in which the radical RHg--is attachedto a cyclic alkaloid of the quinoline group, where R represents anaromatic structure to a carbon atom of which the mercury is directlyattached and in which none of the carbon atoms has direct linkage withany element other than hydrogen, carbon and mercury.

7. A new aromatic mercury compound in which the radical RHg-is attachedto a cyclic alkaloid of the tropine group, where R. represents anaromatic structure to a carbon atom of which .the mercury is directlyattached and in which none of the carbon atoms has direct linkage withany element other than hydrogen, carbon and mercury.

8. A new aromatic mercury compound in which the radical RI-Ig-isattached to a cyclic alkaloid of the iso-quinoline group, where Rrepresents an aromatic structure to a carbon atom of which the mercuryis directly attached and in which none of the carbon atoms has directlinkage with any element other than hydrogen, carbon and mercury.

9. A new phenylmercury compound in which the radical CaHsHg-is attachedto a cyclic alkaloid.

10. A new phenylmercury compound in which the radical CsHsHgis attachedto a cyclic alkaloid of the qulnoline group.

11. A new phenylmercury compound in which the radical CaHsHg-is attachedto a cyclic alkaloid of the tropine group.

12. A new phenylmercury compound in which the radical CaHsHg-iS attachedto a cyclic alkaloid of the iso-quinoline group.

13. Phenylmercury quinine.

14. Phenylmercury atropine.

15. Phenylmercury papaverine.

CARL N. ANDERSEN.

